ABSTRACT Alzheimer's disease (AD) is increasing in prevalence in the United States and despite efforts to date an effective treatment remains elusive. AD presents clinically as amyloid plaque load, neurofibrillary tangles comprised of hyper phosphorylated tau, and abnormal vasculature, but the mechanistic basis for cognitive decline is not known. We have shown that the anti-aging intervention of caloric restriction (CR) preserves brain volume and neuronal synaptic density, and lowers age-related astrogliosis. Importantly, age-related shifts in redox metabolism and mitochondrial energy metabolism in brain are abrogated by CR. Our hypothesis is that neuroprotection by CR will slow AD pathology development specifically through its impact on brain metabolism. We will implement CR in APP PS1 (amyloid plaques) and hTauP301 (neurofibrillary tangles) mouse models of AD to determine the impact of CR-induced changes in brain metabolism on pathology development and the consequence for cellular networks of neurons, glia, and the vasculature. Experiments include behavioral testing, ex vivo electrophysiology, and in vivo imaging technology. Brain metabolism will be tracked using histochemistry and 2-photon metabolic imaging. Additional mechanistic studies using pharmacological and genetic approaches in primary neurons and astrocytes will determine the impact of metabolism on brain cell-cell networks. There are three specific aims: Specific Aim 1: To determine the impact of CR on AD pathology advance, documenting hippocampal dependent memory and behaviors, ex vivo measures of synaptic transmission and hippocampal neuronal networks, and brain metabolism. Specific Aim 2: To determine the impact of metabolism and AD pathology on neuron-glial crosstalk using co-cultured primary neurons and primary astrocytes. Live imaging studies will investigate how neurons with amyloidopathy and tauopathy respond to changes in astrocyte metabolism in real time. Specific Aim 3: To determine the in vivo impact of CR-induced changes in brain metabolism and AD pathology on vascular responsivity and adaptation using implanted transparent electrodes and opto-genetics coupled with coherence tomography. These studies focus on the interaction between disease pathology and the local brain metabolic environment, acknowledging the importance of layers of communication among neuronal, neuron-glia, and vascular networks, and establishing mechanisms behind the neuroprotective effects of CR. The proposed research will advance our understanding of the role metabolism plays in AD progression, and will determine if strategies to preserve brain metabolism as a function of age might have therapeutic potential as a means to ameliorate outcomes of AD, translating basic biology to clinical promise.